Anhydrate of tiotropium bromide

ABSTRACT

Novel Anhydrate The present invention relates to a novel form of anhydrous tiotropium bromide, processes for the preparation of anhydrous tiotropium bromide, pharmaceutical compositions comprising anhydrous tiotropium bromide and uses of the compositions.

CROSS-REFERENCE TO RELATED APPLICATION(s)

This is a Section 371 National Stage Application of International No.PCT/GB2010/051310, filed on 6 Aug. 2010, and published as WO 2011/015882A1 on 10 Feb. 2011, which claims priority from IN Patent Application No.1048/KOL/2009, filed 7 Aug. 2009, the contents of which are incorporatedherein in their entirety for all purposes.

FIELD OF THE INVENTION

The present invention relates to a novel form of anhydrous tiotropiumbromide, processes for the preparation of anhydrous tiotropium bromide,pharmaceutical compositions comprising anhydrous tiotropium bromide anduses of the compositions.

BACKGROUND OF THE INVENTION

Tiotropium bromide (1), first disclosed in EP0418716, is a highlyeffective anticholinergic agent with specificity for muscarinicreceptors and it is presently approved for the treatment of respiratorydisorders, such as asthma or chronic obstructive pulmonary disease(COPD), including chronic bronchitis and emphysema.

Tiotropium bromide is used in low (microgram) therapeutic doses and itis therefore particularly necessary to develop an industrial process forthe commercial preparation of tiotropium bromide which ensures that theproduct is prepared not only in a high, economical yield but also withexceptional chemical and polymorphic purity.

The manufacturing process for many pharmaceuticals is hindered by thefact that the organic compound, which is the active ingredient, hashandling difficulties during the manufacturing process and may impartundesirable properties to the final drug or dosage form. In addition itcan be difficult to control the polymorphic form of the activepharmaceutical ingredient throughout the manufacturing process.

For pharmaceuticals in which the active ingredient can exist in morethan one polymorphic or crystalline form, it is particularly importantto ensure that the manufacturing process for the active ingredientaffords a single, pure polymorph with a consistent level of polymorphicpurity. If the manufacturing process leads to a polymorph with varyingdegrees of polymorphic purity and/or or where the process does notcontrol polymorphic interconversion, serious problems in dissolutionand/or bioavailability can result in the finished pharmaceuticalcomposition comprising the active ingredient.

If crystalline forms are made with polymorphic impurities, this causesinstability and it can accelerate significant interconversion to anotherpolymorphic form. Therefore it is crucial to produce crystalline formswith very high polymorphic purity to avoid this interconversion.

A process for the preparation of tiotropium bromide was first reportedin EP0418716. Tiotropium bromide monohydrate is disclosed inWO2002/30928 along with a method of its preparation by heating anhydroustiotropium bromide in water in the presence of activated charcoal. Inaddition, there have been several subsequent disclosures of methods toprepare anhydrous tiotropium bromide from tiotropium bromide monohydrateor solvate.

A method of preparing anhydrous tiotropium bromide by heating tiotropiumbromide monohydrate at 80-100° C. under vacuum is disclosed in U.S. Pat.No. 6,608,055. However, this method is not suitable for commercialmanufacture as directly heating a solid at high temperature can lead tolocalized heating and inconsistent results.

Another method disclosed in U.S. Pat. No. 6,608,055 involves theconversion of tiotropium bromide monohydrate to anhydrous tiotropiumbromide by storing over silica gel for 24 hours. However, this method isnot amenable to commercial manufacturing.

An alternative method of preparing anhydrous tiotropium bromide,disclosed in WO2007/075858, involves heating tiotropium bromidemethanolate or hemi-n-butanolate or hemi-acetate in an oven at 160° C.This requires very high temperatures and specific solvates as startingmaterial.

Another method, disclosed in US2005/0143410, involves a process forconverting tiotropium bromide monohydrate to anhydrous tiotropiumbromide by boiling in water and adding ammonium fluoride. Alternatively,a crystallization method from methanol with seeding was reported.

A further method, disclosed in US2007/0092453, involves convertingtiotropium bromide monohydrate to anhydrous tiotropium bromide byheating at 50° C. in a 1:1 N,N-dimethylacetamide/water mixture. Alsoreported are 14 different solvates of tiotropium bromide. However, thismethod in US2007/0092453 involves evaporation of high volumes of highboiling solvents at room temperature under a vacuum of 1 Kpa untilcrystals appear in the solution. The method is not particularlyreproducible and as both N,N-dimethylacetamide and water are highboiling solvents (164° C. and 100° C. respectively), the removal ofthese solvents at room temperature requires high vacuum. Thereforeremoval of such volumes of N,N-dimethylacetamide and water at roomtemperature is practically very difficult for production on a commercialscale. In addition, the process is limited to tiotropium bromidemonohydrate as starting material.

From the above prior art details, it can be observed that there is nodirect method reported in the literature for preparing anhydroustiotropium bromide. All the above processes reported for preparinganhydrous tiotropium bromide involve the preparation of eithertiotropium bromide monohydrate or tiotropium bromide solvates asstarting material to prepare anhydrous tiotropium bromide. Thisincreases the number of steps and reduces the overall yield.

Hence it would be advantageous to have a direct method for preparinganhydrous tiotropium bromide which does not involve the preparation ofeither tiotropium bromide monohydrate or a tiotropium bromide solvate asstarting material.

In addition, the processes described in the prior art typically requireelevated temperatures and therefore can lead to impure products, sinceit has been observed that tiotropium bromide decomposes at highertemperatures generating scopine di-(2-thienyl)glycolate as an impurity.Consequently, there is a requirement for an additional purification stepto afford pure anhydrous tiotropium bromide as it typically contains0.1-0.5% of impurity scopine di-(2-thienyl)glycolate. In addition, theanhydrous tiotropium bromide formed in the prior art processes is notpolymorphically pure.

In view of the importance acquired by tiotropium bromide for thetreatment of respiratory disorders, there is a great need for developingan alternative, relatively simple, economical and commercially feasibleprocess for the synthesis of tiotropium bromide crystalline forms withcommercially acceptable yield, chemical purity and high polymorphicpurity and polymorphic stability.

SUMMARY OF THE INVENTION

The inventors have observed that tiotropium bromide forms solvates witha wide range of solvents. Consequently, there is a need for developing adirect synthetic and purification method for anhydrous tiotropiumbromide without using solvents which form solvates.

Therefore the present invention provides an efficient and simple processfor the preparation of anhydrous tiotropium bromide directly withoutgoing through intermediate tiotropium bromide solvates or tiotropiumbromide hydrates such as tiotropium bromide monohydrate.

The present invention also provides a chemically pure andpolymorphically pure and stable form of anhydrous tiotropium bromide.

Surprisingly, the inventors have developed methods which involvesolvents which do not form solvates for the direct preparation ofanhydrous tiotropium bromide and its purification. The methods areshort, very mild and convenient for commercial scale manufacture,particularly as elevated temperatures are avoided for reaction,purification and drying.

The process which has been developed involves the preparation ofanhydrous tiotropium bromide directly from scopinedi-(2-thienyl)glycolate using a very convenient, direct route, withoutthe requirement of an extra synthetic step for initially forming andisolating a hydrate or solvate of tiotropium bromide.

In addition, the method affords a novel crystalline form of anhydroustiotropium bromide which is chemically pure, polymorphically pure andpolymorphically stable.

Accordingly, a first aspect of the present invention provides anhydroustiotropium bromide having an XRPD pattern comprising at least threepeaks (preferably at least four peaks, preferably at least five peaks,preferably at least six peaks, preferably at least seven peaks,preferably at least eight peaks, preferably at least nine peaks,preferably at least ten peaks, preferably at least twelve peaks,preferably at least fifteen peaks, preferably at least twenty peaks,preferably all twenty-two peaks) selected from peaks with 2θ angles ofabout 8.49, 11.38, 13.58, 14.24, 14.74, 16.01, 17.03, 17.93, 18.60,19.15, 21.80, 22.62, 22.92, 23.29, 25.29, 25.57, 26.23, 27.29, 28.07,28.61, 30.24 and 31.83±0.2 degrees. Preferably the first aspect of thepresent invention provides anhydrous tiotropium bromide with an XRPDspectrum substantially as shown in FIG. 1.

Preferably the anhydrous tiotropium bromide according to the firstaspect of the present invention has a DSC spectrum with endothermicpeaks at about 208° C.±2° C. and about 221° C.±2° C. Preferably theanhydrous tiotropium bromide according to the first aspect of thepresent invention has a DSC spectrum substantially as shown in FIG. 2.

Preferably the anhydrous tiotropium bromide according to the firstaspect of the present invention has a TGA spectrum substantially asshown in FIG. 3.

Preferably the anhydrous tiotropium bromide according to the firstaspect of the present invention comprises less than 5% of otherpolymorphic forms of tiotropium bromide, preferably less than 3%,preferably less than 2%, preferably less than 1%, preferably less than0.5%, preferably less than 0.2%, preferably less than 0.1% (as measuredby XRPD).

A second aspect of the present invention provides a process for thepreparation of anhydrous tiotropium bromide, comprising the steps of:

-   -   (a) providing a solution of scopine di-(2-thienyl)glycolate and        a first organic solvent;    -   (b) adding a solution of methyl bromide in a second organic        solvent to the mixture from step (a) or vice versa;    -   (c) isolating anhydrous tiotropium bromide from the mixture        obtained in step (b); and    -   (d) drying the isolated anhydrous tiotropium bromide.

Preferably the first and second organic solvents are not the same.

Preferably the first organic solvent is a ketone, preferably acetone,methyl ethyl ketone, methyl n-propyl ketone, methyl isopropyl ketone,methyl vinyl ketone, methyl n-butyl ketone, methyl isobutyl ketone,methyl tert-butyl ketone or diethyl ketone. Most preferably the firstorganic solvent is acetone.

Preferably the second organic solvent is a polar aprotic solvent,preferably acetonitrile.

In step (b), a solution of methyl bromide in a second organic solvent isadded to the mixture from step (a) or alternatively the mixture fromstep (a) is added to a solution of methyl bromide in a second organicsolvent. Preferably a solution of methyl bromide in a second organicsolvent is added to the mixture from step (a).

Preferably the drying temperature is between about 40 to 80° C., morepreferably about 60° C.

Preferably the process of the second aspect of the present inventioncomprises an additional process for further purifying the anhydroustiotropium bromide.

Preferably the additional process for further purifying the anhydroustiotropium bromide comprises:

-   -   (a) providing a solution of anhydrous tiotropium bromide and a        third organic solvent;    -   (b) adding a fourth organic solvent as an anti-solvent to the        solution from step (a);    -   (c) isolating purified anhydrous tiotropium bromide from the        mixture obtained in step (b); and    -   (d) drying the isolated purified anhydrous tiotropium bromide.

Preferably the third organic solvent is a polar aprotic solvent,preferably dimethylsulfoxide, dimethylformamide or dimethylacetamide.Preferably the third organic solvent is dimethylsulfoxide.

Preferably the fourth organic solvent used as an anti-solvent is aketone, preferably acetone, methyl ethyl ketone, methyl n-propyl ketone,methyl isopropyl ketone, methyl vinyl ketone, methyl n-butyl ketone,methyl isobutyl ketone, methyl tert-butyl ketone or diethyl ketone.Preferably the ketone is acetone.

Preferably the drying temperature used in the additional process forfurther purifying the anhydrous tiotropium bromide is between about 40to 80° C. Preferably the drying temperature is about 60° C.

Preferably the process according to the second aspect of the presentinvention provides anhydrous tiotropium bromide with a yield of at least80% from the starting material (scopine di-(2-thienyl)glycolate),preferably at least 90%, preferably at least 95%, preferably at least96%, preferably at least 97%, preferably at least 98%.

A third aspect of the present invention provides a process of purifyinganhydrous tiotropium bromide, comprising the steps of:

-   -   (a) providing a solution of anhydrous tiotropium bromide and an        organic solvent;    -   (b) adding a further organic solvent as an anti-solvent to the        solution from step (a);    -   (c) isolating purified anhydrous tiotropium bromide from the        mixture obtained in step (b); and    -   (d) drying the isolated purified anhydrous tiotropium bromide.

Preferably the organic solvent used in step (a) is a polar aproticsolvent, preferably dimethylsulfoxide, dimethylformamide ordimethylacetamide, preferably dimethylsulfoxide.

Preferably the organic solvent used in step (b) as an anti-solvent is aketone, preferably acetone, methyl ethyl ketone, methyl n-propyl ketone,methyl isopropyl ketone, methyl vinyl ketone, methyl n-butyl ketone,methyl isobutyl ketone, methyl tert-butyl ketone or diethyl ketone.Preferably the ketone is acetone.

Preferably the drying temperature used in step (d) is between about 40to 80° C. Preferably the drying temperature is about 60° C.

Preferably the process according to the third aspect of the presentinvention provides purified anhydrous tiotropium bromide with a yield ofat least 80% from the starting material (crude anhydrous tiotropiumbromide), preferably at least 90%, preferably at least 95%, preferablyat least 96%, preferably at least 97%, preferably at least 98%.

A fourth aspect of the present invention provides anhydrous tiotropiumbromide comprising less than 0.5% of impurity scopinedi-(2-thienyl)glycolate, preferably less than 0.3%, preferably less than0.2%, preferably less than 0.1%, preferably less than 0.05%, and mostpreferably less than 0.03% (as measured by HPLC).

A fifth aspect of the present invention provides anhydrous tiotropiumbromide with an HPLC purity of at least 98%, preferably at least 99%,preferably at least 99.5%, preferably at least 99.6%, preferably atleast 99.7%, preferably at least 99.8%, preferably at least 99.9%.

Preferably the processes according to the second and third aspects ofthe present invention provide anhydrous tiotropium bromide according tothe first, fourth or fifth aspects of the present invention.

A sixth aspect of the present invention provides anhydrous tiotropiumbromide prepared by a process according to the second or third aspect ofthe present invention. Preferably the anhydrous tiotropium bromide isprepared in a yield of at least 80% from the starting material (scopinedi-(2-thienyl)glycolate or tiotropium bromide), preferably at least 90%,preferably at least 95%, preferably at least 96%, preferably at least97%, preferably at least 98%.

Preferably the anhydrous tiotropium bromide according to the fourth,fifth and sixth aspects of the present invention has an XRPD patterncomprising at least three peaks (preferably at least four peaks,preferably at least five peaks, preferably at least six peaks,preferably at least seven peaks, preferably at least eight peaks,preferably at least nine peaks, preferably at least ten peaks,preferably at least twelve peaks, preferably at least fifteen peaks,preferably at least twenty peaks, preferably all twenty-two peaks)selected from peaks with 2θ angles of about 8.49, 11.38, 13.58, 14.24,14.74, 16.01, 17.03, 17.93, 18.60, 19.15, 21.80, 22.62, 22.92, 23.29,25.29, 25.57, 26.23, 27.29, 28.07, 28.61, 30.24 and 31.83±0.2 degrees.Preferably the anhydrous tiotropium bromide according to the fourth,fifth and sixth aspects of the present invention has an XRPD spectrumsubstantially as shown in FIG. 1.

Preferably the anhydrous tiotropium bromide according to the fourth,fifth and sixth aspects of the present invention has a DSC spectrum withendothermic peaks at about 208° C.±2° C. and about 221° C.±2° C.Preferably the anhydrous tiotropium bromide according to the fourth,fifth and sixth aspects of the present invention has a DSC spectrumsubstantially as shown in FIG. 2.

Preferably the anhydrous tiotropium bromide according to the fourth,fifth and sixth aspects of the present invention has a TGA spectrumsubstantially as shown in FIG. 3.

Preferably the anhydrous tiotropium bromide according to the first,fourth and fifth aspects of the present invention is prepared by aprocess according to the second or third aspect of the presentinvention.

Preferably the anhydrous tiotropium bromide according to the first,fifth and sixth aspects of the present invention comprises less than0.5% of impurity scopine di-(2-thienyl)glycolate, preferably less than0.3%, preferably less than 0.2%, preferably less than 0.1%, preferablyless than 0.05%, and most preferably less than 0.03% (as measured byHPLC).

Preferably the anhydrous tiotropium bromide according to the first,fourth and sixth aspects of the present invention has an HPLC purity ofat least 98%, preferably at least 99%, preferably at least 99.5%,preferably at least 99.6%, preferably at least 99.7%, preferably atleast 99.8%, preferably at least 99.9%.

Preferably the anhydrous tiotropium bromide according to the first,fourth, fifth and sixth aspects of the present invention is suitable foruse in medicine, preferably for the treatment of a respiratory disorder.Preferably the respiratory disorder comprises asthma and COPD.Preferably the COPD includes chronic bronchitis and emphysema.

A seventh aspect of the present invention provides a pharmaceuticalcomposition comprising anhydrous tiotropium bromide according to thefirst, fourth, fifth or sixth aspects of the present invention.Preferably the pharmaceutical composition is suitable for use in a drypowder inhaler (DPI), an aqueous nebulizer or a pressurized metereddosage inhaler (pMDI). Preferably the pharmaceutical composition issuitable for the treatment of a respiratory disorder. Preferably therespiratory disorder comprises asthma and COPD. Preferably the COPDincludes chronic bronchitis and emphysema.

An eighth aspect of the present invention provides the use of anhydroustiotropium bromide according to the first, fourth, fifth or sixthaspects of the present invention or the use of the pharmaceuticalcomposition according to the seventh aspect of the present invention, inthe manufacture of a medicament for the treatment of a respiratorydisorder. Preferably the respiratory disorder comprises asthma and COPD.Preferably the COPD includes chronic bronchitis and emphysema.

A ninth aspect of the present invention provides a method of treating arespiratory disorder, comprising administering to a patient in needthereof a therapeutically effective amount of anhydrous tiotropiumbromide according to the first, fourth, fifth or sixth aspects of thepresent invention or a therapeutically effective amount of thepharmaceutical composition according to the seventh aspect of thepresent invention. Preferably the respiratory disorder comprises asthmaand COPD. Preferably the COPD includes chronic bronchitis and emphysema.Preferably the patient is a mammal, preferably a human.

BRIEF DESCRIPTION OF THE ACCOMPANYING FIGURES

FIG. 1 shows an XRPD spectrum of anhydrous tiotropium bromide accordingto the present invention.

FIG. 2 shows a DSC spectrum of anhydrous tiotropium bromide according tothe present invention.

FIG. 3 shows a TGA spectrum of anhydrous tiotropium bromide according tothe present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a method for preparing anhydroustiotropium bromide directly from scopine di-(2-thienyl)glycolate withoutgoing through tiotropium bromide monohydrate or solvate. Additionally,the present invention provides a method for the purification ofanhydrous tiotropium bromide without solvate formation.

The novel anhydrous form according to the first aspect of the presentinvention does not contain water of crystallization or solvent ofcrystallization as shown by the TGA spectrum in FIG. 3.

A preferred process according to the second aspect of the presentinvention comprises the following steps:

-   -   (a) providing a solution of scopine di-(2-thienyl)glycolate and        acetone;    -   (b) adding a solution of methyl bromide in acetonitrile to the        mixture from step (a);    -   (c) isolating anhydrous tiotropium bromide from the mixture        obtained in step (b); and    -   (d) drying the solid.

Preferably, in order to ensure a complete reaction, scopinedi-(2-thienyl)glycolate should be fully dissolved in the acetone.Preferably this is achieved by stirring acetone and scopinedi-(2-thienyl)glycolate at 25-30° C. High volumes (for example 20 to 50volumes, preferably about 35 volumes) of acetone may preferably be usedto keep the reaction mixture clear to ensure complete conversion.

Preferably, in step (b), a 50% w/w solution of methyl bromide inacetonitrile is employed, preferably at a temperature of 25-30° C.Preferably about 5 volumes of the 50% w/w solution of methyl bromide inacetonitrile are used.

The inventors have also found that stirring the mixture in step (b),preferably for 22 to 26 hours and most preferably for about 24 hours, tofacilitate complete conversion is particularly advantageous.

Isolation of the resulting anhydrous tiotropium bromide in step (c) iseffected in preferred embodiments by filtration. In further preferredembodiments the isolated anhydrous tiotropium bromide is dried inconditions that do not cause anhydrous tiotropium bromide to degrade. Incertain preferred embodiments the anhydrous tiotropium bromide is driedunder conditions of reduced pressure, preferably at 55-65° C. Mostpreferably the anhydrous tiotropium bromide is dried at about 60° C.

The anhydrous tiotropium bromide is very pure, but optionally it can befurther purified by the steps of:

-   -   (a) providing a solution of anhydrous tiotropium bromide and        dimethylsulfoxide;    -   (b) adding acetone as an anti-solvent to the solution from step        (a);    -   (c) isolating purified anhydrous tiotropium bromide from the        mixture obtained in step (b); and    -   (d) drying the solid.

Preferably the anhydrous tiotropium bromide is dissolved indimethylsulfoxide at 25-30° C. Preferably about 2 volumes ofdimethylsulfoxide are used.

Preferably an anti-solvent, preferably acetone, is added to the abovesolution to precipitate the solid. Preferably about 20-30 volumes ofacetone are used, preferably about 25 volumes.

Isolation of the resulting purified anhydrous tiotropium bromide in step(c) is effected in preferred embodiments by filtration. In furtherpreferred embodiments the isolated purified anhydrous tiotropium bromideis dried in conditions that do not cause anhydrous tiotropium bromide todegrade. In certain preferred embodiments the anhydrous tiotropiumbromide is dried under conditions of reduced pressure, preferably at55-65° C. Most preferably the anhydrous tiotropium bromide is dried atabout 60° C.

The polymorphic form of the anhydrous tiotropium bromide does not changeduring the further purification process.

It has been found that purification of crude anhydrous tiotropiumbromide by dissolving in dimethylsulfoxide and precipitating withacetone reduces the level of scopine di-(2-thienyl)glycolate to below0.1%, preferably less than 0.05%, and most preferably less than 0.03%(as measured by HPLC). The inventors have also found that thisparticular solvent combination surprisingly does not form a solvate withtiotropium bromide.

According to a further aspect of the present invention there is providedhighly polymorphically pure anhydrous tiotropium bromide comprising lessthan 5% of other polymorphic forms of tiotropium bromide, preferablyless than 3%, preferably less than 2%, preferably less than 1%,preferably less than 0.5%, preferably less than 0.2%, and mostpreferably less than 0.1% of other polymorphic forms of tiotropiumbromide (as measured by XRPD).

The crystalline anhydrous tiotropium bromide form in accordance with theinvention can be used to advantage in the preparation of pharmaceuticaldosage or drug forms. When in particulate form, the crystalline form inaccordance with the present invention is stable and free flowing anddoes not present any of the stability (e.g. polymorphic conversion orchemical conversion) or handling difficulties associated with the priorart forms. The crystalline form according to the invention, therefore,can be employed in the manufacture of pharmaceutical compositions thatdo not suffer from the problems, such as inconsistent drug substancedissolution rates and the like, that can be manifest in dosage formsmanufactured using previously available forms of tiotropium bromide.

The DPI compositions of the present invention preferably contain, inaddition to the active substance, the following physiologicallyacceptable excipients: monosaccharides (e.g. glucose or arabinose),disaccharides (e.g. lactose, sucrose, maltose), oligo- andpolysaccharides (e.g. dextran), polyalcohols (e.g. sorbitol, mannitol,xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures ofthese excipients with one another. Preferably mono- or disaccharides areused, while the use of lactose or glucose is preferred, particularly inthe form of their hydrates. For the purposes of the present invention,lactose is the particularly preferred excipient, while lactosemonohydrate is most particularly preferred.

Preferably the pMDI of the present invention uses HFA 134a, HFA 227 ormixtures thereof as propellant gas.

The pharmaceutical compositions of the present invention preferablycontain about 0.001 to 20% tiotropium bromide in admixture with one ormore physiologically acceptable excipients. Preferred compositionscontain 0.01 to 10% of tiotropium bromide, more preferred arecompositions which contain 0.01 to 2% of tiotropium bromide, and mostpreferred are compositions which contain 0.04 to 0.8% of tiotropiumbromide.

The following examples are provided to illustrate the present inventionand should not be construed as limiting thereof.

EXAMPLES

As used herein the term “1 volume” or “1 vol” means that for each gramof starting material 1 ml of solvent is used. The terms “2 volumes” or“2 vol” and “3 volumes” or “3 vol” etc. are used accordingly.

Preparation of Anhydrous Tiotropium Bromide from Scopinedi-(2-thienyl)glycolate

Scopine di-(2-thienyl)glycolate (1 eq) was dissolved in acetone (35 vol)at 25-30° C. and methyl bromide in acetonitrile (50% w/w solution, 5vol) was added. The mixture was stirred at 25-30° C. for 24 hours andthe precipitated solid was filtered and washed with acetone (5 vol). Thesolid was dried at 60° C. under vacuum to afford the product as a whitesolid. The crude anhydrous tiotropium bromide obtained was found to havethe XRPD, DSC and TGA spectra shown in FIGS. 1, 2 and 3 respectively.

Molar yield=95%

HPLC purity=99.5-99.7%

Purification of Anhydrous Tiotropium Bromide

Crude anhydrous tiotropium bromide (1 eq) was taken in DMSO (2 vol) andstirred for 1 hour at 25-30° C. Acetone (25 vol) was slowly added andthe mixture was chilled to 0-5° C. and stirred at 0-5° C. for 30minutes. The solid was filtered and washed with acetone (3 vol) anddried under vacuum at 60° C. for 12 hours. The purified anhydroustiotropium bromide obtained was found to have the XRPD, DSC and TGAspectra shown in FIGS. 1, 2 and 3 respectively.

Molar yield=98%

HPLC purity≧99.9%

The crude and purified samples of anhydrous tiotropium bromide preparedin the above examples were found to be substantially purepolymorphically with no levels of other forms detected (>99.7%polymorphically pure, as measured by XRPD). The purified anhydroustiotropium bromide prepared was also found to be very stable chemicallyand polymorphically with no conversion over time to other polymorphs.The stability of the sample was tested by subjecting the sample toaccelerated stability conditions (40° C.±2° C. temperature and 75%±5%relative humidity) for 6 months. The chemical purity (measured byrelated substances and purity assays by HPLC) and polymorphic purity(measured by XRPD, DSC and TGA) were monitored for 6 months and thesample was found to be chemically and polymorphically stable even after6 months under accelerated stability conditions.

The XRPDs were recorded on a Bruker D8 Advance Diffractometer, using CuKα1 radiation as the X-ray source and LynxEye as the detector, with a 2θrange of from 3° to 50°, a step-size of 0.05° and a time/step of 1 sec.

The DSCs were recorded on a Perkin Elmer Pyris 6 Instrument over atemperature range of from 25° C. to 250° C. at a rate of heating of 10°C./min.

The TGAs were recorded on a Perkin Elmer Pyris 1 Instrument over atemperature range of from 25° C. to 250° C. at a rate of heating of 10°C./min.

It will be understood that the present invention has been describedabove by way of example only. The examples are not intended to limit thescope of the invention. Various modifications and embodiments can bemade without departing from the scope and spirit of the invention, whichis defined by the following claims only.

The invention claimed is:
 1. Anhydrous tiotropium bromide having an XRPDpattern comprising at least three peaks selected from peaks with 2θangles of about 8.49, 11.38, 13.58, 14.24, 14.74, 16.01, 17.03, 17.93,18.60, 19.15, 21.80, 22.62, 22.92, 23.29, 25.29, 25.57, 26.23, 27.29,28.07, 28.61, 30.24 and 31.83±0.2 degrees, wherein the anhydroustiotropium bromide comprises: (i) an XRPD spectrum substantially asshown in FIG. 1; and/or (ii) a DSC spectrum with endothermic peaks atabout 208° C.±2° C. and about 221° C.±2° C.; and/or (iii) a DSC spectrumsubstantially as shown in FIG. 2; and/or (iv) a TGA spectrumsubstantially as shown in FIG.
 3. 2. Anhydrous tiotropium bromideaccording to claim 1, comprising: (i) less than 5% of other polymorphicforms of tiotropium bromide; and/or (ii) less than 3% of otherpolymorphic forms of tiotropium bromide; and/or (iii) less than 2% ofother polymorphic forms of tiotropium bromide; and/or (iv) less than 1%of other polymorphic forms of tiotropium bromide; and/or (v) less than0.5% of other polymorphic forms of tiotropium bromide; and/or (vi) lessthan 0.2% of other polymorphic forms of tiotropium bromide; and/or (vii)less than 0.1% of other polymorphic forms of tiotropium bromide. 3.Anhydrous tiotropium bromide according claim 1, comprising: (i) lessthan 0.5% of impurity scopine di-(2-thienyl)glycolate; and/or (ii) lessthan 0.3% of impurity scopine di-(2-thienyl)glycolate; and/or (iii) lessthan 0.2% of impurity scopine di-(2-thienyl)glycolate; and/or (iv) lessthan 0.1% of impurity scopine di-(2-thienyl)glycolate; and/or (v) lessthan 0.05% of impurity scopine di-(2-thienyl)glycolate; and/or (vi) lessthan 0.03% of impurity scopine di-(2-thienyl)glycolate.
 4. Anhydroustiotropium bromide according to claim 1, having an HPLC purity of: (i)at least 98%; and/or (ii) at least 99%; and/or (iii) at least 99.5%;and/or (iv) at least 99.6%; and/or (v) at least 99.7%; and/or (vi) atleast 99.8%; and/or (vii) at least 99.9%.
 5. A process for thepreparation of anhydrous tiotropium bromide according to claim 1,comprising the steps of: (a) providing a solution of scopinedi-(2-thienyl)glycolate and a first organic solvent; (b) adding asolution of methyl bromide in a second organic solvent to the mixturefrom step (a) or vice versa; (c) isolating anhydrous tiotropium bromidefrom the mixture obtained in step (b); and (d) drying the isolatedanhydrous tiotropium bromide.
 6. A process according to claim 5,wherein: (i) the first organic solvent is a ketone such as acetone;and/or (ii) the second organic solvent is acetonitrile; and/or (iii) thedrying temperature is between about 40 to 80° C., or is about 60° C. 7.A process according to claim 5, comprising an additional process forfurther purifying the anhydrous tiotropium bromide, optionally whereinthe additional process for further purifying the anhydrous tiotropiumbromide comprises: (a) providing a solution of anhydrous tiotropiumbromide and a third organic solvent; (b) adding a fourth organic solventas an anti-solvent to the solution from step (a); (c) isolating purifiedanhydrous tiotropium bromide from the mixture obtained in step (b); and(d) drying the isolated purified anhydrous tiotropium bromide.
 8. Aprocess according to claim 7, wherein: (i) the third organic solvent isdimethylsulfoxide; and/or (ii) the fourth organic solvent used as ananti-solvent is a ketone such as acetone; and/or (iii) the dryingtemperature is between about 40 to 80° C., or is about 60° C.
 9. Aprocess of purifying anhydrous tiotropium bromide according to claim 1,comprising the steps of: (a) providing a solution of anhydroustiotropium bromide and an organic solvent; (b) adding a further organicsolvent as an anti-solvent to the solution from step (a); (c) isolatingpurified anhydrous tiotropium bromide from the mixture obtained in step(b); and (d) drying the isolated purified anhydrous tiotropium bromide.10. A process according to claim 9, wherein: (i) the organic solventused in step (a) is dimethylsulfoxide; and/or (ii) the organic solventused in step (b) as an anti-solvent is a ketone such as acetone; and/or(iii) the drying temperature is between about 40 to 80° C., or is about60° C.
 11. Anhydrous tiotropium bromide according to claim 1, for: (i)use in medicine; and/or (ii) the treatment of a respiratory disorder;and/or (iii) the treatment of asthma or COPD; and/or (iv) the treatmentof chronic bronchitis or emphysema.
 12. A pharmaceutical compositioncomprising anhydrous tiotropium bromide according to claim
 1. 13. Apharmaceutical composition according to claim 12, for: (i) use in a drypowder inhaler (DPI), an aqueous nebulizer or a pressurized metereddosage inhaler (pMDI); and/or (ii) the treatment of a respiratorydisorder, such as asthma or COPD, wherein the COPD includes chronicbronchitis and emphysema.
 14. A method of treating a respiratorydisorder, comprising administering to a patient in need thereof atherapeutically effective amount of anhydrous tiotropium bromideaccording to claim
 1. 15. The method according to claim 14, wherein: (i)the respiratory disorder comprises asthma and COPD; and/or (ii) therespiratory disorder is chronic bronchitis or emphysema.